The long-term goal of this project is to discern how the regulation of protein synthesis contributes to skeletal muscle mass under anabolic and catabolic stimuli. Such an understanding is essential for the development of therapeutic strategies to abrogate or reverse the loss of muscle mass associated with conditions such as hormonal imbalance, nutrient insufficiency, and several disease states. There are a number of regulatory agents (e.g. insulin, leucine) that alter skeletal muscle protein synthesis through regulation of mRNA translation. These agents can activate multiple signal transduction pathways to modulate the activation and function of several eukaryotic initiation factors (elF), as well as other proteins involved in translational control. This project proposes to examine the effects of cAMP agonists (e.g. glucagon, epinephrine) on the regulation of translation initiation and protein synthesis in skeletal muscle cells and perfused rat hindlimb skeletal muscle, in the absence and presence of insulin or leucine. We propose to identify the signaling pathways regulated by cAMP (e.g. PKA, ERK, mTOR), and their effects upon the regulation of translation initiation (i.e. elF4F assembly) related to alterations in protein synthesis.